Ann Lab Med.  2015 May;35(3):336-340. 10.3343/alm.2015.35.3.336.

Mutation Analysis of the TGFBI Gene in Consecutive Korean Patients With Corneal Dystrophies

• Song JS
• Lim DH
• Chung ES
• Chung TY
• Ki CS

• KMID: 2363206
• DOI: http://doi.org/10.3343/alm.2015.35.3.336

Abstract

BACKGROUND
Mutations in the transforming growth factor beta-induced gene (TGFBI) are major causes of genetic corneal dystrophies (CDs), which can be grouped into TGFBI CDs. Although a few studies have reported the clinical and genetic features of Korean patients with TGFBI CD, no data are available regarding the frequency and spectrum of TGFBI mutations in a consecutive series of Korean patients with clinically diagnosed CDs.
METHODS
Patients with any type of CD, who underwent both ophthalmologic examination and TGFBI gene analysis by Sanger sequencing at a tertiary care hospital in Seoul, Korea from 2006 to 2013, were enrolled in this study.
RESULTS
Among a total of 89 patients, 77 (86.5%) were diagnosed as having clinical TGFBI CD. Seventy-three out of 74 patients (98.6%) with granular CD type 2 (GCD2), had the p.R124H mutation. Of particular note, one patient with rapidly progressive CD had the p.R124H mutation as well as a novel nonsense variant with unknown clinical significance (p.A179*). In three patients with lattice CD type 1 (LCD1), one known mutation (p.R124C) and two novel variants (p.L569Q and p.T621P) in the TGFBI gene were identified.
CONCLUSIONS
This study provides epidemiological insight into CDs in a Korean population and reaffirms that GCD2 is the most common TGFBI CD phenotype and that p.R124H is the only mutation identified in patients with GCD2. In addition, we broaden the spectrum of TGFBI mutations by identifying two novel missense variants in patients with LCD1.

Keyword

Granular corneal dystrophy type 2; Korean; Lattice corneal dystrophy type 1; Mutation; TGFBI

MeSH Terms

Adolescent
Adult
Aged
Asian Continental Ancestry Group/*genetics
Corneal Dystrophies, Hereditary/diagnosis/*genetics
DNA Mutational Analysis
Female
Humans
Male
Middle Aged
Phenotype
Polymorphism, Single Nucleotide
Republic of Korea
Retrospective Studies
Transforming Growth Factor beta1/*genetics
Young Adult
Transforming Growth Factor beta1

Figure

• 

  Fig. 1 Flow chart of the TGFBI mutation analysis protocol and the results of the 89 patients included in the present study.*The p.A179* mutation was additionally found in one patient with the p.R124H mutation; †Three patients underwent sequence analysis of only exon 4.

• 

  Fig. 2 Sequence electrophoerograms of novel TGFBI variants. (A) The c.535C>T (p.A179*) variant identified in a patient with granular corneal dystrophy type 2 (arrow). (B) The c.1706T>A (p.L569Q) variant identified in a patient with lattice corneal dystrophy, TGFBI type (arrow). (C) The c.1861A>C (p.T621P) variant identified in a patient with lattice corneal dystrophy, TGFBI type (arrow).

• 

  Fig. 3 Slit-lamp photographs. (A) Patient with GCD2 without any TGFBI mutations and a few discrete granular deposits in the anterior stroma with unilateral manifestation. (B) Patient with GCD2 carrying a novel p.A179* variant, as well as the p.R124H mutation, with progressed granular opacities in a dense confluent pattern covering most of the corneal surface. (C) Patient with LCD1, carrying the p.L569Q variant and large lattice lines. (D) Patient with LCD1, carrying the p.T621P variant with recurrent corneal erosions with typical lattice lines.

Reference

1. Zhang T, Yan N, Yu W, Liu Y, Liu G, Wu X, et al. Molecular genetics of Chinese families with TGFBI corneal dystrophies. Mol Vis. 2011; 17:380–387. PMID: 21311742.

2. Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009; 4:7. PMID: 19236704.

3. Weiss JS, Moller HU, Lisch W, Kinoshita S, Aldave AJ, Belin MW, et al. The IC3D classification of the corneal dystrophies. Cornea. 2008; 27:S1–S83. PMID: 19337156.

4. Zhu Y, Shentu X, Wang W. The TGFBI R555W mutation induces a new granular corneal dystrophy type I phenotype. Mol Vis. 2011; 17:225–230. PMID: 21264234.

5. Abazi Z, Magarasevic L, Grubisa I, Risovic D. Individual phenotypic variances in a family with Avellino corneal dystrophy. BMC Ophthalmol. 2013; 13:30. PMID: 23837658.

6. Aldave AJ, Sonmez B. Elucidating the molecular genetic basis of the corneal dystrophies: are we there yet? Arch Ophthalmol. 2007; 125:177–186. PMID: 17296893.

7. Nowinska AK, Wylegala E, Janiszewska DA, Dobrowolski D, Aragona P, Roszkowska AM, et al. Genotype-phenotype correlation of TGFBI corneal dystrophies in Polish patients. Mol Vis. 2011; 17:2333–2342. PMID: 21921985.

8. Yoshida S, Yoshida A, Nakao S, Emori A, Nakamura T, Fujisawa K, et al. Lattice corneal dystrophy type I without typical lattice lines: role of mutational analysis. Am J Ophthalmol. 2004; 137:586–588. PMID: 15013897.

9. Kim HS, Yoon SK, Cho BJ, Kim EK, Joo CK. BIGH3 gene mutations and rapid detection in Korean patients with corneal dystrophy. Cornea. 2001; 20:844–849. PMID: 11685063.

10. Jun RM, Tchah H, Kim TI, Stulting RD, Jung SE, Seo KY, et al. Avellino corneal dystrophy after LASIK. Ophthalmology. 2004; 111:463–468. PMID: 15019320.

11. Lee JH, Cristol SM, Kim WC, Chung ES, Tchah H, Kim MS, et al. Prevalence of granular corneal dystrophy type 2 (Avellino corneal dystrophy) in the Korean population. Ophthalmic Epidemiol. 2010; 17:160–165. PMID: 20455845.

12. Cho KJ, Mok JW, Na KS, Rho CR, Byun YS, Hwang HS, et al. TGFBI gene mutations in a Korean population with corneal dystrophy. Mol Vis. 2012; 18:2012–2021. PMID: 22876129.

13. Han KE, Kim TI, Chung WS, Choi SI, Kim BY, Kim EK. Clinical findings and treatments of granular corneal dystrophy type 2 (avellino corneal dystrophy): a review of the literature. Eye Contact Lens. 2010; 36:296–299. PMID: 20724852.

14. Holland EJ, Daya SM, Stone EM, Folberg R, Dobler AA, Cameron JD, et al. Avellino corneal dystrophy. Clinical manifestations and natural history. Ophthalmology. 1992; 99:1564–1568. PMID: 1454323.

15. Yam GH, Wang K, Jhanji V, Choy KW, Baum L, Pang CP. In vitro amyloid aggregate forming ability of TGFBI mutants that cause corneal dystrophies. Invest Ophthalmol Vis Sci. 2012; 53:5890–5898. PMID: 22850414.

16. Vincent AL, de Karolyi B, Patel DV, Wheeldon CE, McGhee CN. TGFBI mutational analysis in a New Zealand population of inherited corneal dystrophy patients. Br J Ophthalmol. 2010; 94:836–842. PMID: 19948560.

17. Sakimoto T, Kanno H, Shoji J, Kashima Y, Nakagawa S, Miwa S, et al. A novel nonsense mutation with a compound heterozygous mutation in TGFBI gene in lattice corneal dystrophy type I. Jpn J Ophthalmol. 2003; 47:13–17. PMID: 12586172.